03 November 2005

A number of cases have been reported in which patients are said to have damaged or destroyed areas of body afflicted by neuropathic pain and sensory deficit (the latter being an inevitable accompaniment of the former) (see Mailis, 1996).

In 30 years of pain clinic practice with a particular emphasis on neuropathic pain, I have seen two only patients in whom ‘self-injurious behaviour’ (Mailis, 1996) has occurred. Patient 1 was one of 160 patients with central post-stroke pain (CPSP) personally seen and examined by myself; Patient 2 was one of 282 patients with postherpetic neuralgia (PHN) personally seen and examined by myself.

Patient 1 was a right-handed man who had a stroke at age 66 affecting the left side of his body, including the face. He was aphasic, and remained so for 6 weeks; he had hiccoughs which persisted for 2 or 3 months. There was severe loss of power in his left arm and leg.

Burning and shooting pain appeared in the left side of his face some 3 months later.

He was first seen in the Pain Clinic 2 years after the stroke. By this time his motor deficit was almost imperceptible. He still complained of burning and shooting pains in the left side of the face, particularly at the tip of his nose; he also had occasional pins and needles in his left arm and even less frequently in his left leg. He stated that his facial pain was exacerbated by drinking hot liquids; that the left side of his face always felt hot, and sometimes went red for 3 or 4 weeks at a time. On examination, tactile and sharpness sensations were diminished on the left side of the face, particularly on the outer lower left side of his nose, and to a lesser extent in his left arm. There was no clinically evident deficit of temperature sensation.

The ala nasae of the left nostril was absent, leaving a half-moon-shaped gap extending about 7.5 mm up the nose in comparison with the right side. He said that he had ‘picked and pulled’ at his nostril ever since the pain came on, because that was where the pain was worst. His GP confirmed that this self-inflicted mutilation had occurred since the central post-stroke pain came on. The patient averred that he still felt pain in the ‘missing part’ of his nose.

He had had a stellate ganglion block and an intravenous infusion of lignocaine in another hospital before being referred to us; neither had had any effect on his pain. We prescribed nortriptyline, rising to 75 mg nocte. This also had no effect, and the patient discharged himself after 3 months.

Patient 2 was an apparently phlegmatic male farmer born in 1912 who had herpes zoster affecting his right ophthalmic nerve (V1) in 1984, at the age of 72. When seen in the Pain Clinic 2 years later, aged 74, he had some mild backache but was otherwise an extremely healthy man, still working. He complained of a pain on the right side of his forehead which he described on his McGill Questionnaire as "Throbbing, boring, pressing, pulling, and hot". He had some mild dynamic tactile allodynia. Amitriptyline, rising to 50 mg nocte, was prescribed. When next seen in a follow-up clinic, a few months later, he stated that he felt ‘much better’. However, the following year he had a mild stroke, which resulted in him being treated with Madopar® 62.5 mg b.d.

He was next seen in the Pain Clinic 9 months later (now aged 75). There were no evident symptoms or signs of stroke; he was then taking a proprietary drug containing both an anticholinergic and a calcium channel blocker. His forehead pain was still described as ‘much better’.

Beginning 3 months later, he complained that he ‘couldn't feel the right side of his forehead’. He had begun to scratch the area, resulting in red scratchmarks. When asked why he did this, he denied that there was any pain or itching, but said that as he couldn't feel anything, he wanted ‘to make sure it was still there’. Clinical testing confirmed the absence of tactile and sharpness sensations, and severe diminution of temperature sensation; an area about 3 cm wide and 4 cm wide centred above the middle of the right eyebrow could be said to be virtually anaesthetic.

He was seen at frequent intervals over the next 4 years. Within 18 months, he had scratched his forehead down to the bone in circular area of about 1.5 cm diameter about 2.5 cm above the middle of the right eyebrow, surrounded by a rectangular area in which injury changed centripetally from down to periosteum to more superficial cutaneous layers. He prevented the process of healing by repeated scratching. He repeatedly denied that he felt any pain, but said that there was some ‘irritation’. As he was clean-shaven, he was asked whether or not he didn't think that seeing his forehead in a shaving mirror every morning confirmed that it was indeed present. He admitted this, but said it had become a habit during the day to touch and subsequently scratch, harder and harder, to see if he could elicit any sensation which would confirm its presence. Medical treatment with both external applications of benzydamine and lignocaine creams, and systemically with tricyclics, carbamazepine, baclofen, and buprenorphine had no effect; neither did transcutaneous nerve stimulation, stellate ganglion or supraorbital nerve blocks.Discussion

Neither of our patients was assessed by a clinical psychologist. However, both appeared to be of normal intelligence; both were married men doing responsible jobs. They may well have been exogenously depressed by their illness, but showed no obvious clinical signs of endogenous depression at interview. They thus did not overtly exhibit two of the criteria listed by Mailis (1996) for self-injurious behaviour (SIB): low intelligence and depressive personality.

Many of the cases of SIB reported in the literature (which has been extensively reviewed by Mailis, 1996) were of ‘ulcers’ and ‘excoriations’. Injury of this sort is undoubtedly under-reported. However, both the cases reported here had extensive and unequivocal injuries. It is interesting, and perhaps significant, that both involve the face, for by far the greatest number of reported self-inflicted injuries are facial, in patients with anaesthesia dolorosa following destructive procedures of the trigeminal ganglion.

Prima facie, it would seem that the first patient reported herein was a genuine case of autotomy; he destroyed a painful part, in which he subsequently continued to have phantom pain.

The second patient, however, mutilated an area from which he had no apparent sensory input. This is an extreme case of a much commoner clinical phenomenon: following peripheral nerve injury resulting in an anaesthetic area of skin, most patients take no notice of it, except to remark, if directly questioned, that they have an area in which there is no feeling. A small number, however, become obsessed with a perfectly painless but anaesthetic area. The patient reported here is such a case, although the only one in our experience who has injured himself as a result.

However, another case involving a patient with HZ-PHN has been reported to me anecdotally by Dr R.W. Johnson (Bristol). This concerns an elderly man who had facial zoster, and subsequently had violent itching in his analgesic right ala nasae. Because he could feel no pain, scratching the itch eventually resulted in excavation of the lower outer border of the nose.

These cases are clearly not autotomy as commonly defined (the term is not included in either the first (Merskey, 1986) or second ( Mersky and Bogduk, 1994) edition of the IASP Classification of Chronic Pain). The term as now used in neurological/pain medicine appears to have been introduced by Wall et al. (1979), although they did not limit it to a phenomenon occurring only in supposed neuropathic pain, as now is the case.

There is an implication for experimental animal work, in which it is well-known (but rarely reported) that of animals subjected to nerve ligation and other subtotal nerve injuries, only a proportion exhibit signs of neuropathic pain, and of this proportion, only a few perform autotomy. If an animal chews off an extremity, how do we know whether it is doing so because the extremity hurts, or because it regards an anaesthetic part as a foreign body, and rids itself of it? This would appear to be the conclusion from the work of Shir et al. (2001), who found that autotomy only occurs in rats with completely denervated hindlimbs. The best argument against such an interpretation has been put forward by Blumenkopf and Lipman (1991) on the basis of animal studies, but cannot be justified by experience with human patients. The present case 2 had no pain in the mutilated area, and I do not regard it as a case of autotomy, whereas case 1 not only had pain in the mutilated area, but continued to experience such pain in the missing ala nasae after SIB, thus raising the interesting question of the relationship between pain in an area of partial sensory deficit and phantom pain.

With these insights into the basis of pain insensitivity, stoics will patiently await the unravelling of the genetic basis of the clinically less pressing, but philosophically more interesting problem of congenital indifference to pain. – John Wood, 1996

Congenital indifference to pain, also referred to as congenital universal insensitivity to pain, has been reported since the early 1930s (Dearborn; Ford; Boyd; McMurray; Ogden; Landrieu and Davis). These individuals typically have painless injuries beginning in infancy, but normal sensory responses on examination. Perception of passive movement, joint position, and vibration is normal, as are tactile thresholds and light touch perception. The ability to distinguish sharp and dull stimuli and detect differences in temperature seems to be intact ( McMurray and Ogden). Reflexes and autonomic responses are also normal.

Peripheral nerve samples were obtained from several of the earlier cases of congenital indifference to pain, and no abnormalities were observed (Ogden et al., 1959). Because of their seemingly normal neurologic examinations, these individuals were considered to have a deficit in the affective response to pain rather than in the sensory discrimination of painful stimuli. However, because morphometric analysis of nerve fiber size density had not been performed, it is unclear whether selective loss of nerve fibers was present. There have been mixed results with some biopsies reported as abnormal ( Low and Dyck) and it is possible that some cases are HSAN V. Because of the possibility of peripheral neuropathy, these cases are therefore not considered definitive examples of indifference to pain ( Dyck and Thomas).

A case of congenital indifference to pain with normal nerve morphology has been described by Landrieu et al. (1990). The patient was a 5-year-old girl with painless fractures and indifference to ‘casual injuries’. Withdrawal reflexes and grimacing were present to pinprick and hot water (43°C), but she was indifferent to prolonged or repeated application of the painful stimuli anywhere on her body. Subcutaneous injection of histamine yielded normal results. She had an otherwise normal neurological examination. She detected pinprick, heat, and cold, and responded normally to light touch, joint position, vibration, and pressure. Her reflexes were normal, no autonomic abnormalities were observed, and cortical sensory evoked potentials were normal. A sural nerve biopsy appeared normal using electron microscopy, and the size density distributions appeared normal for both myelinated and unmyelinated fibers. In addition, she was reported to have normal psychomotor development.

The normal electron microscopic nerve morphometry rules out the possibility of a selective absence of unmyelinated nociceptors, although it does not exclude the possibility of other structural or neurochemical abnormalities. This patient demonstrates that congenital indifference to pain does not require the same type of peripheral nerve abnormalities associated with the hereditary sensory neuropathies. As Thomas (1993) has suggested, such patients ‘could represent a disturbance affecting neurotransmitters that did not involve loss of nerve fibers, or … the differences could be due to an abnormality of the central sensory pathways or processing’. Additionally, the case suggests that abnormal pain responses can occur even though pain discrimination, affect, and withdrawal responses appear preserved.

Davis et al. (1998) described a subject with normal perception of pinprick, light touch, and vibration. In addition to lifelong lack of pain perception with accompanying painless injuries, she had gait disturbance and spasticity. Sural nerve biopsy and electrophysiologic studies were normal. At age 56, she had progressive decline in cognitive abilities. Autopsy conducted at age 62 showed evidence of Alzheimer's disease and thalamic gliosis at multiple levels, including both ventral and midline nuclei. The amount of gliosis exceeded that found in age-matched normal brains and in an Alzheimer's disease control brain. Other family members were reported to have similar symptoms, including a lack of response to painful stimuli. Although complicated by the presence of other neurologic symptoms, this report suggests that deficits present in hereditary pain insensitivity and indifference disorders can have central as well as peripheral origins.6. Asymbolia for pain and related conditions

When lesions occur in the areas of the brain that subserve the processing of painful stimuli, deficits in one or more of the components of pain perception can occur, and disorders similar to congenital pain insensitivity can result. Lesions in the anterior cingulate cortex or insular cortex impact the medial pain system and, thus, might be expected to cause a loss of the affective-motivational component. Lesions in the primary and secondary somatosensory cortex affect the lateral pain system; their expected major effect would be loss of sensory-discriminative components of pain.

Loss of the affective-motivational component of pain has been called ‘asymbolia for pain’. An early report described a patient who showed a lack of responsiveness to strong electrical currents and physically threatening gestures (Schilder and Stengel, 1931). Although there was some reaction to pain, no withdrawal responses occurred, and the patient at times ‘even seemed to derive some pleasure’ from the painful stimuli. The authors described both the ‘pain reaction’ and the ‘appreciation of pain’ as inadequate, and attributed pain asymbolia to findings of parietal lobe lesions in this patient and two others who were studied.

Later authors restricted use of the term ‘asymbolia for pain’ to patients with deficits in the affective-motivational component of pain but preserved sensory discrimination. Such patients perceive painful stimuli but lack emotional responses and withdrawal movements (Berthier et al., 1988). As in the earlier descriptions, some patients reportedly smiled or laughed in response to noxious stimuli. Computed tomography demonstrated insular cortex lesions in all patients in a series of six such patients ( Berthier et al., 1988). Lesions in the secondary somatosensory cortex could have explained a lack of response to painful stimuli, but no such abnormalities were found in two of these patients.

It is also possible that central lesions could impair the sensory-discriminative components of pain while sparing affective-motivational components. Ploner et al. (1999) describe a patient with a lesion in the primary and secondary somatosensory areas subserving the left hand. He had normal heat pain thresholds in the right hand, but did not perceive pain in the left hand, even at temperatures much higher than those used on his unaffected side. He showed deficits in the assessment of both stimulus localization and quality in the left hand. When offered a list of prompts including both painful and non-painful thermal descriptors, the patient would not use any of them to describe the stimulus, nor could he locate the stimulus more specifically than ‘between fingertips and shoulder’.

However, when stimulus intensities equal to and greater than what he considered painful on the unaffected side were administered to the left hand, the patient described a ‘clearly unpleasant’ feeling that he wanted to avoid. This finding suggests that the affective-motivational component of pain was intact and is consistent with the lateral pain system, which includes the somatosensory cortex, being more involved in the sensory-discriminative component of pain than in pain affect. This case also illustrates that it is possible for pain responses to occur without an intact sensory-discriminative system.7. Conclusions

The deficits present in the different pain insensitivity syndromes provide insight into the complex anatomical and physiological nature of pain perception. Reports of pain asymbolia and related cortical conditions illustrate that there can be losses that independently involve either the sensory-discriminative component or the affective-motivational component of pain perception, thus highlighting their different anatomical localization. The presentations of congenital indifference to pain and pain asymbolia overlap, which suggests that indifference to pain – whether congenital or acquired – may involve one or more deficits preferentially affecting the components of the medial pain system, which includes the anterior cingulate cortex.

By affecting both the lateral and medial pain systems, the peripheral nerve abnormalities observed in individuals with the various types of HSAN cause deficits in both components of pain perception. The case of Ploner et al. (1999) demonstrates that the affective-motivational component can be retained even in the absence of the sensory-discriminative component. Importantly, this suggests that the absence of affective responses in individuals with HSAN is not simply a consequence of loss of sensory discrimination but also involves loss of input to the medial pain system caused by the peripheral neuropathy.

It has been proposed that the affective component of pain is not unitary and consists of at least two stages, an immediate primary stage and a cognitively-mediated second stage (Price, 1999). In the cases reviewed, it is unclear at which stage the observed deficits originate. Careful assessment of the separate components of pain sensory intensity and unpleasantness in patients with various congenital pain insensitivity and indifference disorders will help to further clarify the pathways underlying the different components of pain perception. In addition, mapping genetic defects in HSAN patients will provide important clues about molecular mechanisms of pain, and the promise of new, more effective and selective therapies.

02 November 2005

In my dissertation I argue that the traditional account of pain's intrinsic badness --i.e., pain is bad because disliked; because unpleasant; because represents damage, et cetera-- are like the famous three blind men and the elephant. When we have the correct conception of what pain is, we can see that all of these (and other quasi-motivational states like fear) are the source of pain's intrinsic badness. For my reference, and your pleasure, here's

John Godfrey Saxe's ( 1816-1887) version of the famous Indian legend,It was six men of IndostanTo learning much inclined,Who went to see the Elephant(Though all of them were blind),That each by observationMight satisfy his mind.

The First approached the Elephant,And happening to fallAgainst his broad and sturdy side,At once began to bawl:"God bless me! but the ElephantIs very like a wall!"

The Second, feeling of the tuskCried, "Ho! what have we here,So very round and smooth and sharp?To me `tis mighty clearThis wonder of an ElephantIs very like a spear!"

The Third approached the animal,And happening to takeThe squirming trunk within his hands,Thus boldly up he spake:"I see," quoth he, "the ElephantIs very like a snake!"

The Fourth reached out an eager hand,And felt about the knee:"What most this wondrous beast is likeIs mighty plain," quoth he;"'Tis clear enough the ElephantIs very like a tree!"

The Fifth, who chanced to touch the ear,Said: "E'en the blindest manCan tell what this resembles most;Deny the fact who can,This marvel of an ElephantIs very like a fan!"

The Sixth no sooner had begunAbout the beast to grope,Than, seizing on the swinging tailThat fell within his scope."I see," quoth he, "the ElephantIs very like a rope!"

And so these men of IndostanDisputed loud and long,Each in his own opinionExceeding stiff and strong,Though each was partly in the right,And all were in the wrong!

Moral:

So oft in theologic wars,The disputants, I ween,Rail on in utter ignoranceOf what each other mean,And prate about an ElephantNot one of them has seen!